Practice Essentials

A mosquito-borne disease (see the image below), yellow fever can manifest as a spectrum of presentations ranging from asymptomatic illness to acute-onset viral hepatitis and hemorrhagic fever.
[1, 2]

This female Aedes aegypti mosquito is shown after landing on a human host. The A aegypti mosquito is a known transmitter of dengue fever and yellow fever. A aegypti is sometimes referred to as the yellow fever mosquito. The viruses are transferred to the host when he or she has been bitten by a female mosquito. Image courtesy of the CDC/World Health Organization (WHO).

Signs and symptoms

Yellow fever is usually a mild, self-limiting illness consisting of fever, headache, myalgia, and malaise. More serious illness presents with the abrupt onset of the following:

General malaise

Fever

Chills

Headache

Lower back pain

Nausea

Dizziness

This is followed by a period of remission; the patient may then either recover or progress to fatal illness. The return of symptoms is marked by the following:

Fever

Vomiting

Abdominal pain

Renal failure

Hemorrhage

Physical examination

Physical findings in yellow fever include the following:

Fever

Relative bradycardia for the degree of fever (Faget sign)

Conjunctival injection

Skin flushing

As the disease progresses, additional physical findings include the following:

Scleral icterus

Jaundice

Epigastric tenderness

Hepatomegaly

The following will also often be apparent:

Petechiae

Purpura

Mucosal bleeding

Gastrointestinal bleeding (gross or occult)

Organ ischemia, which primarily affects the kidneys and central nervous system, leads to altered mental status and/or signs of volume overload. In the late stages of yellow fever, patients present with the following:

Tachycardia

Hypothermia or hyperthermia

Hypotension

Individuals who are severely hypoperfused appear mottled and cyanotic; they are also often obtunded. Tachypnea and hypoxia with impending respiratory failure may develop as a consequence of sepsis and acute respiratory distress syndrome (ARDS).

Management

No specific treatment exists for yellow fever; however, supportive care is critical. Severely ill patients should be treated in an intensive care setting. The required management consists of the following:

Background

Yellow fever is one of many causes of viral hemorrhagic fever. It is a member of the flavivirus family (group B arbovirus). The Flavivirus genus is composed of more than 70 arthropod-transmitted viruses, of which 30 are known to cause human disease. Other flaviviral infections include dengue, Japanese encephalitis, and tick-borne encephalitis. It is important to consider this group of viruses in the clinical differential of CNS infection, hemorrhagic fever, and acute febrile illnesses with arthropathy. Yellow fever virus is shown in the image below. (See Etiology.)

Yellow fever virus. Image courtesy of the Centers for Disease Control and Prevention.

A mosquito-borne disease, yellow fever can manifest as a spectrum of presentations, ranging from asymptomatic illness to acute-onset viral hepatitis and hemorrhagic fever. (See Clinical and Workup.)

From 1793-1822, yellow fever was one of the most dreaded diseases in US port cities. Yellow fever outbreaks in the United States shaped American history and influenced important national decisions. In the 1780s, yellow fever outbreaks in Philadelphia were responsible for killing one tenth of the city's population.
[4]

The disease may have played a part in shaping the decision to move the nation's capital out of Philadelphia.
[4] The disease had such an impact on the local economies that, in 1803, Napoleon, with his troops decimated by yellow fever, had few reservations about selling the affected Louisiana and western territories to the US government.

Fascinating accounts document how humankind's struggle with yellow fever has shaped world history. The French effort to develop the Panama Canal was not lost through engineering failures, but by disease. Frenchmen died of yellow fever in alarming numbers, leading to Panama being coined "the white man's graveyard."
[5]

In the early 20th century, Carlos Findlay and Walter Reed's discovery of Aedes aegypti as a source of yellow fever transmission led to the eradication of yellow fever in parts of Latin America. Isolation of the virus and later development of the 17D vaccine by Max Theiler helped to eliminate A aegypti and yellow fever from countries in Africa and the Americas during the mid 20th century.
[6]

Yellow fever is transmitted by tree-hole breeding mosquitoes (Haemagogus and Aedes species) during the tropical wet season and early dry season.
[1] Genomic sequence analyses suggest that yellow fever evolved from other mosquito-borne viruses about 3000 years ago in Africa. It is surmised that the yellow fever virus was introduced to the Americas by Dutch slave traders during the 17th century.

The first documented epidemic occurred in the Yucatan Peninsula and spread through the Caribbean basin. This was the result of ship travel and the continued importation of slaves from West Africa. Vessels infested with A aegypti mosquitoes brought yellow fever into New England and several port cities throughout North America.

Large vaccination campaigns and A aegypti control programs have decreased the incidence of yellow fever worldwide. Nonetheless, yellow fever has reemerged across Africa and South America, despite the availability of an effective live-attenuated 17D vaccine. The populations at highest risk for the illness are those in countries that lack the funding and infrastructure to support a widespread vaccination program. (See Epidemiology and Treatment.)
[7, 8]

Flaviviruses, including those that cause yellow fever, also have a potential use as biologic weapons.
[9]

Transmission

As an arthropod-borne virus (ie, arbovirus), yellow fever is transferred from host to host by contaminated mouthparts of mosquitoes. Different species of the Aedes and Haemagogus genus breed in unique habitats. For example, Aedes aegypti, the first identified vector of yellow fever, is able to breed in small amounts of temporary standing water and, thus, in close association with humans.

In contrast, other mosquitoes are forest canopy dwellers and thrive only in rainforests. Consequently, these vectors transmit the virus in 3 ways: (1) between monkeys, (2) from monkeys to humans, and (3) from person to person.
[10, 11] This variability has led to 3 types of transmission cycles (depicted in the diagram below): sylvatic (jungle), intermediate (savannah), and urban. (See the diagram below.)

Sylvatic (jungle) cycle

In tropical rainforests, yellow fever virus is endemic among lower primates. Infected monkeys pass the virus to mosquitoes that feed on them. Persons who subsequently enter the forest (often workers, eg, loggers, and travelers) are infected with this form of disease. In Africa, the principal vector of the jungle cycle is A africanus; in South America, H janthinomys is the primary vector for jungle transmission. Nonhuman primates remain the preferred host in this setting.

Intermediate (savannah) cycle

In moist and semihumid areas of Africa, semi-domestic mosquitoes (which breed in the wild and around households) feed primarily on monkeys but will also feed on humans when the opportunity arises. This cycle likely reflects the evolution of yellow fever into an epidemic human disease. It is the most common cycle present in Africa and frequently leads to small-scale outbreaks in villages. However, transmission can potentially lead to large-scale epidemics if an infected individual carries the disease into an urban region. This cycle has not been identified in South America.

Urban cycle

A aegypti is responsible for the transmission of urban yellow fever in Africa and South America. This mosquito can breed in urban water containers, allowing mosquito transmission of the yellow fever virus from human to human. Thus, A aegypti can infect large populations of unvaccinated individuals. Urban outbreaks are rare in South America, yet they are still occasionally reported in densely populated regions in Africa. (See the image below.)

This female Aedes aegypti mosquito is shown after landing on a human host. The A aegypti mosquito is a known transmitter of dengue fever and yellow fever. A aegypti is sometimes referred to as the yellow fever mosquito. The viruses are transferred to the host when he or she has been bitten by a female mosquito. Image courtesy of the CDC/World Health Organization (WHO).

Etiology

Yellow fever virus is a positive-sense, single-stranded, ribonucleic acid (RNA) ̶ enveloped flavivirus with a diameter of about 50-60 nm. The virus is transmitted via the saliva of an infected mosquito. Local replication of the virus takes place in the skin and regional lymph nodes. Viremia and dissemination follow.

The virus gains entrance through receptor-mediated endocytosis. RNA synthesis occurs in the cytoplasm and protein synthesis takes place in the endoplasmic reticulum. Virions are released through the cell membrane. The viral envelope contains a lipid bilayer taken from the infected cell. Virulence factors include the following:

Capsid protein C - Facilitates viral binding

Membrane protein M - A minor glycoprotein

E proteins - Initiate infection and mediate viral entry

Nonstructural protein 1 (NS1) - May play a role in RNA replication

NS2A protein - Involved in RNA replication and packaging

NS2B and NS3 - Form a complex and are involved in polyprotein processing and replication of RNA

NS5 - Has a major role in RNA replication

The E protein interacts with the cellular receptor, and virions are endocytosed into the dendritic cells. Subsequently, epidermal dendritic cells and lymph channels disseminate virions. After invasion in the host, Kupffer cells (fixed liver macrophages) are infected within 24 hours.

The liver is the most important organ affected in yellow fever. The disease was labeled "yellow" based on the profound jaundice observed in affected individuals. Hepatocellular damage is characterized by lobular steatosis, necrosis, and apoptosis with subsequent formation of Councilman bodies (degenerative eosinophilic hepatocytes).
[12]

The kidneys also undergo significant pathologic changes. Albuminuria and renal insufficiency evolve secondary to the prerenal component of yellow fever; consequently, acute tubular necrosis develops in advanced disease. Hemorrhage and erosion of the gastric mucosa lead to hematemesis, popularly known as black vomit. Fatty infiltration of the myocardium, including the conduction system, can lead to myocarditis and arrhythmias.

Central nervous system (CNS) findings can be attributed to cerebral edema and hemorrhages compounded on metabolic disturbances. The bleeding diathesis of this disease is secondary to reduced hepatic synthesis of clotting factors, thrombocytopenia, and platelet dysfunction. The terminal event of shock can be attributed to a combination of direct parenchymal damage and a systemic inflammatory response.

Finally, circulatory shock develops secondary to cytokine storm, with evidence of increased levels of interleukin (IL)-6, IL-1 receptor antagonist, interferon-inducible protein-10, and tumor necrosis factor (TNF)–alpha. Viral antigens are found diffusely in kidneys, myocardium, and hepatocytes. In individuals who survive yellow fever, the recovery is complete, with no residual fibrosis.

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Epidemiology

Occurrence in the United States

Reports of yellow fever in the United States are exceedingly rare, with the last outbreak reported in New Orleans in 1905. It is a rare cause of illness in returning travelers; between 1970-2002, 9 cases of yellow fever were reported in unimmunized travelers from the United States and Europe. In these individuals, the disease was acquired in Brazil, Senegal, Venezuela, Ivory Coast, Gambia, and West Africa. Seven of these cases were fatal.
[11, 3]

World Health Organization (WHO) data suggest that the rate of yellow fever transmission is increasing, especially in sub-Saharan Africa. In addition, the number of US residents traveling to South America and Africa is also increasing. The WHO estimates that travelers from the United States to endemic areas has doubled since 1988.
[13] Without proper precautions, including vaccination, these travelers are at risk of contracting yellow fever.

Less fervent mosquito control efforts in the United States have led to the reemergence of Aedes aegypti in the last 30 years. A aegypti has been found in 23 states in the southeastern US. It is still a common mosquito in subtropical regions of southeastern Florida and along the Gulf of Mexico.
[10, 14]

After 21st century outbreaks of dengue fever in Hawaii and along the Texas-Mexico border, it has been hypothesized that yellow fever could reemerge in the United States.
[15] Virology research has isolated Flaviviridae strains from mosquitoes in eastern Texas, making transmission of urban yellow fever a potential threat for the United States in the future.
[16]

International occurrence

After adjustment for underreporting, an estimated 200,000 cases of yellow fever occur annually, with 30,000 deaths per year.
[10] Accurate incidence reporting is limited by the occurrence of asymptomatic disease, underreporting of the disease, and lack of diagnostic capabilities in endemic areas.
[3]

Ninety percent of reported cases occur in Africa,
[17] where Aaegypti is rampant. Transmission occurs in largely unvaccinated populations of sub-Saharan Africa. The countries at greatest risk lie within a band from 15° north to 10° south of the equator.
[18] This region includes 32 countries in sub-Saharan Africa. (See the image below).
[10]

Global distribution of yellow fever. Image courtesy of the Centers for Disease Control and Prevention.

Thirty-three countries in Africa are at risk. Transmission in Africa is facilitated by the close proximity of vector mosquito populations to unvaccinated human populations.
[17] The case-fatality rate of yellow fever in Africa approximates 20%. Infants and children are at highest risk.
[19]

In South America, the rate of transmission of yellow fever is lower than in Africa. Historically, yellow fever outbreaks in South America occurred in the Amazon region.
[3] The Haemagogus species of mosquitoes transmitted the virus in this area; affected individuals developed the sylvatic form of yellow fever.
[18] Most of these cases occurred in young men working in the forests.

Yellow fever is endemic in 9 South American countries and several Caribbean islands. Bolivia, Brazil, Ecuador, and Peru are considered at highest risk.
[17] The incidence of yellow fever in South America is lower than in Africa because the infected monkeys in the rain forest canopy do not often come in contact with human populations. Indigenous human populations have immunity as a part of mass immunization campaigns.
[19] Yellow fever occurs most frequently in young men through occupational exposure in forested areas.

Recent outbreaks in urban areas of South America have been due to deforestation, population migration, and the resultant emergence of A aegypti species. Currently, 13 endemic countries within South America have been identified, with Bolivia, Brazil, Columbia, Ecuador, and Peru at greatest risk.
[10] The range of yellow fever continues to expand, now including areas in which it previously was believed to be eradicated (eg, eastern and southern African countries). Although yellow fever has never been reported in Asia, this region is at risk because the appropriate primates and mosquitoes are present.
[18]

Outbreaks of yellow fever have not been reported in Asia, but this region remains at risk because of the presence of competent vector mosquitoes and nonhuman primates.
[17]

A traveler's risk of acquiring yellow fever depends on the location of travel, immunization status, season, duration of travel, and types of occupational or recreational activities. For travelers, the risk of illness and death due to yellow fever is estimated to be 10 times greater in West Africa than in South America.
[19]

Though transmission rates vary by year and season, it is estimated that an unvaccinated traveler spending 2 weeks in sub-Saharan Africa carries a 1:267 risk of contracting yellow fever, with a 1:1333 risk of death from illness. The corresponding risks for persons traveling to South America are about 10% lower.
[20]

US travel data from 1996-2004 describes the overall risk for serious illness and death due to yellow fever estimated to be 0.05-0.5 per 100,000 travelers to yellow fever–endemic areas.
[19]

Sex-related demographics

South American cases of yellow fever are sporadic and usually occur in the population exposed to tropical rain forests. Men aged 14-45 years are most often infected through occupational exposure.
[18]

In African cases, in which undervaccination of endemic populations has led to higher infection rates in children, yellow fever is slightly more common in males.

Age-related demographics

African cases of yellow fever occur seasonally in villages in contact with semidomestic mosquitoes. In these populations, nonimmunized children are at the highest risk.

Sylvatic disease primarily affects individuals aged 15-45 years who work outdoors in agriculture and forestry. Urban yellow fever and intermediate yellow fever, which occurs primarily in the humid savannas of Africa, affect individuals of all ages.
[18]

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Prognosis

Yellow fever ranges in severity from a self-limited infection to life-threatening hemorrhagic fever. About 15-25% of affected individuals develop a more severe phase of disease that involves fever, jaundice, and liver and renal failure. Case-fatality rates in South America are reportedly higher than in West Africa.
[3] Mortality is a function of patient susceptibility and of the virulence of the infecting strain.
[12]

The case-fatality rate for yellow fever has been reported at 5%-70%. In recent outbreaks, the fatality rate was approximately 20% among patients with jaundice. The mortality risk in patients who present in the toxic stage of yellow fever is up to 50%.
[21]

Death usually follows within 7-10 days of the onset of the toxic phase of yellow fever; however, mortality is a function of host susceptibility and the virulence of the infecting strain.
[12] Infancy and age older than 50 years is associated with increased severity of illness and lethality.
[3]

Unvaccinated travelers entering endemic regions have a greater risk of developing symptomatic disease than natives who have developed significant immunity.
[1] An association has been made between recurrent outbreaks in West Africa and a unique strain in that region, suggesting that it may be more virulent in humans.
[17]

The rare cases of postvaccination neurologic and system disease have infrequently led to death. Most individuals diagnosed with yellow fever vaccine-associated neurologic disease (YEL-AND) recover withoout sequelae; the case-fatality rate has been reported as less than 5%. Even fewer cases of fatal yellow fever vaccine-associated viscerotropic disease (YEL-AVD) have been documented.
[3, 22]

Complications

Complications include:

Liver failure

Renal failure

Pulmonary edema

Myocarditis

Secondary bacterial infections

Hemorrhage or disseminated intravascular coagulation

Encephalitis (rare)

Shock or death

Secondary bacterial infections are frequent complications in patients who survive the critical period of illness.

Yellow fever virus. Image courtesy of the Centers for Disease Control and Prevention.

This female Aedes aegypti mosquito is shown after landing on a human host. The A aegypti mosquito is a known transmitter of dengue fever and yellow fever. A aegypti is sometimes referred to as the yellow fever mosquito. The viruses are transferred to the host when he or she has been bitten by a female mosquito. Image courtesy of the CDC/World Health Organization (WHO).

Global distribution of yellow fever. Image courtesy of the Centers for Disease Control and Prevention.